Multicomponent reactions studies: Yonemitsu-type trimolecular condensations promoted by Ti(IV) derivatives

Article abstract of DOI:10.1016/j.tet.2010.02.025

We have developed a Ti(IV)/Et₃N-promoted trimolecular condensation of aromatic heterocycles (furan, pyrrole, imidazole, indole) with aldehydes and active methylene compounds. In the case of indole and methyl acetoacetate the reaction afforded three-component products or tricyclic cyclopenta[b]indole derivative, depending on the reaction conditions. In both cases, NMR analysis evidenced that titanium enolate is the reactive species involved in the reaction.

Full text of DOI:10.1016/j.tet.2010.02.025

Tetrahedron 66 (2010) 3065–3069
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Tetrahedron
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Multicomponent reactions studies: Yonemitsu-type trimolecular condensations
promoted by Ti(IV) derivatives
a
,
a
,
b
a
c
c
*
´
´
´
`
Stephane Gerard , Andrea Renzetti , Berangere Lefevre , Antonella Fontana , Paolo de Maria ,
,
Janos Sapi a
*
a
´
´
´
Institut de Chimie Moleculaire de Reims, UMR CNRS 6229, Universite de Reims-Champagne-Ardenne, Faculte de Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims, Cedex, France
b Department of Chemistry, Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
c
`
Dipartimento di Scienze del Farmaco, Universita ‘G. d’Annunzio’, via dei Vestini 33, I-66100 Chieti, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a Ti(IV)/Et3N-promoted trimolecular condensation of aromatic heterocycles (furan,
pyrrole, imidazole, indole) with aldehydes and active methylene compounds. In the case of indole and
methyl acetoacetate the reaction afforded three-component products or tricyclic cyclopenta[b]indole
derivative, depending on the reaction conditions. In both cases, NMR analysis evidenced that titanium
enolate is the reactive species involved in the reaction.
Received 23 December 2009
Received in revised form 2 February 2010
Accepted 3 February 2010
Available online 8 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
new heterocyclic scaffolds, we tested some aldehydes, heterocycles,
and activated carbonyl compounds in the presence of two Ti(IV)
Multicomponent reactions (MCRs) are one-pot reactions where
three or more molecules react in the same reaction vessel affording
a single product without isolation of any intermediate.1 This ap-
proach combines multiple advantages like operationally simple and
easily automatable procedure, requiring readily available starting
materials and final work-up only. Moreover, as this methodology is
also characterized by high atom economy and exploratory power, it
became a method of choice especially in drug discovery.2 Even if
titanium(IV) reagents are widely used in organic synthesis for C–C
bond formation or functional group transformations,3 their utili-
zation as promoters in multicomponent approach has been rarely
investigated.4,5
derivatives.
R1CHO
O
O
R1
OR2
TiCl4/Et3N
OR2
R3
N
H
N
H
R3
R1= Alkyl, aryl, ...
R2 = Me, Et, ...
R3 = CO2Et, COMe, NO2, P(O)(OEt)2
Scheme 1. TiCl4/Et3N-promoted trimolecular condensation.
The Yonemitsu condensation of indole with Meldrum’s acid and
an aldehyde is an example of multicomponent reaction.6 This re-
action combined with simple functional group transformations can
2. Results and discussion
The TiCl4/Et3N system promotes the trimolecular condensation
of furan, isobutyraldehyde, and diisopropyl malonate or methyl
acetoacetate in 65% and 71% yield, respectively (Table 1, entries 1
and 2). With these encouraging results in hand we were keen to
investigate whether pyrrole derivatives were compatible with such
conditions. Even if pyrrole is more reactive than furan toward
electrophiles, the yield of condensation products 3c and 3d (Table 1,
entries 3 and 4) is much lower (13%) probably due to the poly-
merization of pyrrole derivatives in the presence of strong Lewis
acid.10 For this reason, we decided to decrease the acidity of the
titanium promoter by replacing chlorine atoms with more hin-
dered and less electronegative isopropoxide groups. Titanium(IV)
isopropoxide was discarded owing to its very low activity observed
in a previous study.9 Consequently, we turned to TiCl2(O-iPr)2,
be used to synthesize various b-substituted tryptophans, b-carbo-
lines, and carbazoles of biological interest.7,8 We have recently
reported its TiCl4/Et3N-promoted version using aldehydes, aro-
matic heterocycles, and various active methylene compounds
(Scheme 1).9 By this way the Yonemitsu condensation has been
extended to active methylene derivatives, e.g., malonesters, nitro-
acetates or triethylphosphonoacetate, non-reactive species under
classical conditions (D,L-proline, CH3CN). To further explore the
scope and limitations of this methodology for the preparation of
* Corresponding authors. Tel.: þ33 3 26 91 87 07; fax: þ33 3 26 91 80 29; e-mail
´
addresses: stephane.gerard@uiv-reims.fr (S. Gerard), janos.sapi@univ-reims.fr (J. Sapi).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.025

3066
S. Ge´rard et al. / Tetrahedron 66 (2010) 3065–3069
Table 1
promote the three-component reaction with less reactive partners
like furans or methyl-2-pyrrolecarboxylate (Table 1, entries 1, 2, and
5). We found that imidazole and 2-methylimidazole in the presence
of TiCl2(O-iPr)2 smoothly afforded three-component products (3f
and 3g) thus opening the way to the preparation of histidine de-
rivatives or imidazole condensed heterocycles (Table 1, entries 6
and 7). Similarly, switching from TiCl4 to TiCl2(O-iPr)2 to promote
the condensation reaction with 4-fluorobenzaldehyde or tetronic
acid allowed to improve the chemical yields of the corresponding
trimolecular adducts 3h and 3i to 72% and 85% yield, respectively
(Table 1, entries 8 and 9).
Trimolecular condensation of heterocycles, aldehydes, and active methylene
compounds promoted by Ti(IV) derivatives
R1 CO2R3
R2
R1
H
TiCl4 or TiCl2(OiPr)2
O
CO2R3
R2
Het.
Et3N, CH2Cl2, 3Å
0°C to r.t.
Het.
3a-h
Entry
1
Condensation product
Yielda (%)
TiCl4
TiCl2(O-iPr)2
Knoev.
Considering the synthetic utility of
b
-ketoesters,11 their re-
CO iPr
2
3a
3b
3c
3d
3e
3f
65
O
CO iPr
activity with indole and various aldehydes has also been in-
vestigated (Table 2). Thus, the reaction of methyl acetoacetate with
indole and isobutyraldehyde in the presence of 1 equiv of TiCl4 at
room temperature afforded the corresponding trimolecular adduct
4a in 45% yield after 30 min stirring (Table 2, entry 1).9 These ex-
perimental conditions could successfully be extended to benzal-
dehyde and 2-nitrobenzaldehyde giving trimolecular adducts 4b
and 4c with satisfactory yields (Table 2, entries 1, 5, and 8). Sur-
prisingly, a longer (about 3 h) reaction time led to an unexpected
new condensation product that we unambiguously identified as
a tricyclic derivative 5a (Table 2, entry 2). Tricyclic compounds 5b
and 5c could also be selectively obtained under the same experi-
mental conditions with aromatic aldehydes (Table 2, entries 6 and
9). Three-component derivative 5c may be versatile for the syn-
thesis of new pentacyclic ring systems by subsequent nitro group
reduction and cyclization. However, the TiCl2(O-iPr)2-promoted
version of this approach afforded only trimolecular derivatives 4a–
c, even if the reactions were carried out overnight (Table 2, entries
3, 4, 7, and 10). The fact that such polyfunctionalized 2,3-cyclo-
pentene-annulated indole core was accessible only by laborious
manner12 our trimolecular methodology may offer new perspec-
tives in heterocyclic chemistry.
From mechanistic point of view, TiCl4-promoted trimolecular
condensation is likely to take place in three steps, namely (i) enolate
formation; (ii) Knoevenagel condensation between this reactive
species and the aldehyde; (iii) Michael addition of indole to the
Knoevenagel adduct. The proposed mechanism is the same that we
have recently studied in an analogous reaction13 and could confirm
the formation of the diastereomerically pure bicyclic product 4a
bearing isopropyl and methoxycarbonyl groups in anti position after
equilibration in the reaction mixture.14 In the case of aromatic al-
dehydes, additionalsteric constraints couldexplaintheobservedlow
diastereoselectivity for compounds 4b and 4c (unseparable mixture
of the two diastereomers in 80/20 and 50/50 ratio, respectively).
The mechanism of the TiCl2(O-iPr)2-promoted condensation
seemed to be analogous to that observed in the presence of TiCl4
involving the generation of the reactive enolate ion. This hypothesis
is supported by NMR analysis. Indeed, when 1.0 equiv of diiso-
propyl malonate was added to a solution of TiCl2(O-iPr)2 in CDCl3,
both TiCl2(O-iPr)2 and diester signals shifted to lower fields (from
2
CO2Me
2
3
4
5
6
71
d
O
O
CO2iPr
CO2iPr
13
88
NH
N
CO2iPr
CO2iPr
Traces
90
Bn
CO2iPr
CO2iPr
34
Knoev.
NH
CO2Me
CO iPr
2
Traces
33
CO iPr
2
N
N
HN
CO iPr
2
7
8
3g
3h
CO iPr
d
52
72
2
HN
F
CO iPr
2
14
CO iPr
2
N
H
O
O
d
4.92 to 5.00 ppm and d 3.26 to 3.72 ppm, respectively) in accord
9
3i
d
85
with the formation of a complex of lower electron density.15 Ad-
dition of 1.0 equiv of triethylamine provoked the formation of an
orange solution of enolate. The signal corresponding to the enolate
OH
N
H
a
Yield refers to chromatographically purified product. Knoev.: Knoevenagel ad-
duct; (d) no condensation product observed.
a
hydrogen (at around d 4.30 ppm) disappeared after quenching
with DCl. 13C NMR spectra were in agreement with proton spectra:
complexation with Ti resulted in the deshielding of methylene
directly prepared in the reaction medium by mixing equal amount
of TiCl4 and Ti(O-iPr)4. We were pleased to find that the trimo-
lecular condensation between pyrrole, isobutyraldehyde, and dii-
sopropyl malonate occurred in good yield (88%) in the presence of
1.0 equiv of TiCl2(O-iPr)2 and 1.0 equiv of Et3N (Table 1, entry 3).
Similarly, high yield was observed with N-benzylpyrrole (Table 1,
entry 4). However, we found that TiCl2(O-iPr)2 was weak to
signal (from
d 38.8 to 42.4 ppm), whereas a second shift from d 42.4
to 69.4 ppm corresponded to the formation of the enolate.
Tricyclic derivatives 5a–c probably arise from an intramolecular
cyclization of the corresponding bicyclic derivatives 4a–c. A plau-
sible mechanism for their formation is depicted in Scheme 2. The
trimolecular condensation involves the conversion of TiCl4 into
13
TiOCl2 that forms a complex (I) with the condensation product.

S. Ge´rard et al. / Tetrahedron 66 (2010) 3065–3069
3067
Table 2
Trimolecular condensation of indole, methyl acetoacetate, and various aldehydes
TiCl4
or
R
H
O
R
R
CO2Me
TiCl2(OiPr)2
CO2Me
CO2Me
O
Conditions
N
H
N
H
N
H
4a-c
O
5a-c
Entry
R
Conditions
Yielda (%)
Compd 4b
Compd 5b
1
2
3
4
TiCl4, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, 30 min
TiCl4, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, 3 h
45
Traces
40
d
48
d
d
TiCl2(O-iPr)2, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, 3 h
TiCl2(O-iPr)2, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, overnight
45
5
6
7
TiCl4, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, 30 min
TiCl4, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, 2 h 30 min
TiCl2(O-iPr)2, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, overnight
49
5
37
Traces
34
Traces
8
9
10
TiCl4, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, 30 min
TiCl4, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, 3 h
41
15
50
d
77
d
TiCl2(O-iPr)2, Et3N, CH2Cl2, 3 Å, 0 ꢀC to rt, overnight
a
Isolated yield after purification by silica gel chromatography.
All new compounds gave satisfactory 1H and 13C NMR, IR, and HRMS or elemental analysis data; (d) no condensation product observed.
b
Complexation increases the electrophilicity of the carbonyl groups
favoring the intramolecular attack of indole to the ketone carbonyl
and the formation of the intermediate II. Finally, a deprotonation
partners. Thus, heteroaromatic derivatives like pyrroles or imidaz-
oles and active methylene compounds (malonates, acetoacetates
or tetronic acid) were successfully incorporated in trimolecular
condensation product. TiCl4/Et3N-promoted reaction of indole,
methyl acetoacetate, and aldehydes with longer reaction time
afforded tricyclic cyclopenta[b]indole derivatives paving the way to
the synthesis of functionalized indole heterocycles of biological
interest. NMR spectral measurements gave a better insight into the
elementarysteps of this three-component reaction. The feasibilityof
an asymmetric version using chiral Ti(IV) ligands is currently under
investigation.
restores the full aromaticity of indole and a b-like elimination leads
to the tricyclic adduct III. There are some experimental evidences
showing that I is not a complex of TiCl4. When isolated 4a was
treated with 1 equiv of TiCl4 in CH2Cl2, the solution changed color,
suggesting the formation of a complex 4a–TiCl4. However, this
complex did not furnish the tricyclic product 5a, even after 24 h of
stirring. Therefore, 4a–TiCl4 is not the intermediate in the forma-
tion of the tricyclic compound.
4. Experimental section
4.1. General
All solvents were dried and purified by standard literature
methods prior to use. Melting points were determined on a Reich-
ert Thermovar hot-stage apparatus and are uncorrected. Reactions
were monitored with Merck TLC aluminum sheets (Kieselgel
60F254) and preparative chromatographies were carried out on
silica gel 60 (70–230 mesh ASTM) supplied by Merck. 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were acquired on
a Bruker AC 300 spectrometer in CDCl3, with TMS as internal
standard. IR spectra (film or KBr) were measured with a PERKIN
ELMER SPECTRUM BX FTIR instrument. Mass spectra were either
recorded with a VG Autospec apparatus or with a GCT Micromass
Waters apparatus. Elemental analyses were carried out by the Mi-
croanalysis Service of the University of Reims.
4.2. General procedure for the trimolecular condensation
promoted by Ti(IV) derivatives
Scheme 2. Proposed mechanism for the formation of the tricyclic compounds 5a–c.
In a typical procedure, the 1,3-dicarbonyl derivative (1.0 equiv) is
added to a solution of TiCl4 (1.0 equiv) in dry dichloromethane
(20 mL/10 mmol) or a mixture of TiCl4 (0.5 equiv) and Ti(O-iPr)4
(0.5 equiv) in dry dichloromethane (20 mL/10 mmol), at 0 ꢀC under
nitrogen using 3 Å molecular sieves. After 20 min, Et3N (1.0 equiv)
was added and the solution became orange. A few minutes later, the
aldehyde (1.0 equiv) was added dropwise and the mixture was
3. Conclusion
Continuing our investigations on Ti(IV)-promoted three-com-
ponent reactions between various heterocycles, aldehydes, and ac-
tive methylene compounds we evidenced TiCl2(O-iPr)2/Et3N system
as an alternative to TiCl4 in the case of incompatibility with reaction

3068
S. Ge´rard et al. / Tetrahedron 66 (2010) 3065–3069
stirred at 0 ꢀC until its disappearance. Finally, the heterocycle
(1.0 equiv) was added and the mixture was allowed to warm up to
room temperature until the reaction was complete (monitored by
TLC). After quenching with an aqueous 1 M HCl solution, the organic
layer was dried over MgSO4 and concentrated under vacuum to give
the crude product. Purification by column chromatography on silica
gel or by recrystallization furnished the corresponding trimolecular
adduct.
1H), 3.86 (d, J¼9.6 Hz, 1H), 4.53 (dd, J¼9.6, 6.0 Hz, 1H), 4.82 (m, 1H),
4.99 (m, 1H), 6.91 (s, 1H), 7.44 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3)
d 17.5, 19.8, 21.0, 21.1, 21.2, 21.3, 30.8, 55.4, 62.3, 69.7, 70.0,
121.6, 128.0, 135.0, 165.8, 166.1 ppm; IR (KBr)
n 3219, 2940, 1639,
1326, 1064, 829, 752 cmꢁ1; MS (EI) m/z 310 [Mꢂþ], 181, 140, 139, 123,
122; HRMS calcd for C16H26N2O4 (Mþ) 310.1893, found: 310.1893.
4.2.7. Isopropyl 2-isopropoxycarbonyl-3-((50-methyl)imidazol-3-yl)-
3-(2-propyl)propanoate 3g. Colorless oil (0.74 g, 52%); 1H NMR
4.2.1. Isopropyl 2-isopropoxycarbonyl-3-(2-furyl)-3-(2-propyl)pro-
(300 MHz, CDCl3)
d
0.85 (d, J¼6.9 Hz, 3H), 0.86 (d, J¼6.9 Hz, 3H),
panoate 3a. Pale yellow oil (0.88 g, 65%); 1H NMR (CDCl3)
d
0.84 (d,
1.05 (d, J¼6.5 Hz, 6H), 1.20 (d, J¼6.3 Hz, 3H), 1.25 (d, J¼6.3 Hz, 3H),
2.17 (m, 1H), 2.40 (s, 3H), 3.85 (d, J¼10.1 Hz, 1H), 4.56 (dd, J¼10.1,
6.3 Hz, 1H), 4.81 (m, 1H), 5.05 (m, 1H), 6.85 (s, 1H), 6.93 (s, 1H) ppm;
J¼6.6 Hz, 3H), 0.87 (d, J¼6.6 Hz, 3H), 1.12–1.27 (m, 12H), 2.09 (m,
1H), 3.51 (dd, J¼10.2, 4.5 Hz, 1H), 3.98 (d, J¼10.2 Hz, 1H), 4.85 (s,
3H), 5.11 (s, 3H), 6.09 (m, 1H), 6.23 (m, 1H), 7.32 (d, J¼2.1 Hz,
13C NMR (75 MHz, CDCl3)
d 13.6, 17.8, 19.7, 21.2, 21.3, 21.4, 21.5, 32.2,
1H) ppm; 13C NMR (CDCl3)
d
17.4, 21.1, 21.4, 21.7, 30.1, 44.6, 55.1,
56.4, 59.5, 69.7, 69.9, 127.2, 153.9, 165.8, 166.4 ppm; IR (KBr) n 3452,
68.7, 68.9,107.7,108.1,141.5,153.1,168.2,168.8 ppm; IR (KBr)
n
2990,
3043, 2987, 1746, 1723, 1274, 1101, 765 cmꢁ1; MS (EI) m/z 324 [Mꢂþ],
218, 158, 140, 122; HRMS calcd for C17H28N2O4 (Mþ) 324.2049,
found: 324.2043.
1765, 1733, 1023 cmꢁ1; MS (CI): m/z 311 [MþH], 267, 223, 174, 136.
C17H26O5 (310.39): calcd C 65.78, H 8.44; found C 66.04, H 8.56.
4.2.2. Methyl 2-(acetyl)-3-(2-furyl)-3-(2-propyl)propanoate 3b. White
4.2.8. Isopropyl 2-isopropoxycarbonyl-3-(indol-3-yl)-3-(4-fluorophe
solid (0.74 g, 71%); mp 90–92 ꢀC; 1H NMR (CDCl3)
d
0.82 (d, J¼6.7 Hz,
nyl)propanoate 3h. Pink solid (2.67 g, 74%); mp 154–155 ꢀC; 1H
3H), 0.88 (d, J¼6.7 Hz, 3H),1.84 (m, 1H), 2.30 (s, 3H), 3.56 (m, 4H), 4.12
(dd, J¼13.5, 11.7 Hz, 1H), 6.08 (d, J¼3.2 Hz, 1H), 6.30 (m, 1H), 7.34 (d,
NMR (300 MHz, CDCl3)
d
0.96 (d, J¼6.2 Hz, 6H), 1.01 (d, J¼6.2 Hz,
3H), 1.11 (d, J¼6.2 Hz, 3H), 4.19 (d, J¼11.7 Hz, 1H), 4.86 (m, 2H), 5.04
J¼1.6 Hz, 1H) ppm; 13C NMR (CDCl3)
d 17.5, 21.6, 29.2, 44.3, 52.3, 61.7,
(d, J¼11.7 Hz, 1H), 6.91–7.52 (m, 9H), 8.14 (s, 1H) ppm; 13C NMR
107.7, 109.9, 141.3, 152.3, 168.5, 201.7 ppm; IR (KBr)
n
2960, 1744,1714,
(75 MHz, CDCl3) d 21.2, 21.4, 41.9, 58.6, 68.9, 69.0, 111.0, 114.9, 115.2,
1458, 1352, 1260, 1159 cmꢁ1; MS (CI): m/z 238, 195, 178, 153, 121;
116.9,119.2, 119.5, 120.7, 122.2, 126.5, 129.8, 136.2, 137.2, 161.5, 167.3,
HRMS calcd for C13H18O4 (Mþ) 238.1205, found: 238.1295.
167.4 ppm; IR (KBr) n 3396, 2970, 1738, 1505, 1335, 1213, 1153, 1099,
735 cmꢁ1; MS (CI) m/z 411 [MþH], 225, 224, 147, 105; HRMS calcd
4.2.3. Isopropyl 2-isopropoxycarbonyl-3-(pyrrol-2-yl)-3-(2-propyl)-
propanoate 3c. Colorless oil (2.38 g, 88%); 1H NMR (300 MHz,
CDCl3) 0.78 (d, J¼6.6 Hz, 3H), 0.93 (d, J¼6.7 Hz, 3H),1.03 (d, J¼6.3 Hz,
3H), 1.08–1.20 (m, 9H), 2.02 (m, 1H), 3.05 (t, J¼7.6 Hz, 1H), 3.82 (d,
J¼7.5 Hz, 1H), 4.89 (m, 1H), 5.04 (m, 1H), 5.86 (m, 1H), 6.01 (m, 1H),
for C24H26NO4F (Mþ) 411.1846, found: 411.1833.
4.2.9. 2-(Indol-3-yl)-2-(2-propyl)tetronic acid 3i. Pale yellow oil
(1.01 g, 85%); 1H NMR (300 MHz, CDCl3)
d
1.02 (d, J¼6.6 Hz, 3H),
1.05 (d, J¼6.6 Hz, 3H), 2.64 (m, 1H), 3.79 (d, J¼9.2 Hz, 1H), 4.42 (AB,
6.65 (m, 1H), 9.16 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 20.2, 21.1,
J¼16.1 Hz, 2H), 7.05–7.34 (m, 4H), 7.62 (d, J¼7.6 Hz, 1H), 8.06 (s,
21.2, 21.4, 21.6, 30.1, 45.9, 54.7, 68.6, 68.7, 106.7, 108.2, 116.6, 129.0,
1H) ppm; 13C NMR (75 MHz, CDCl3)
d 21.4, 21.7, 29.7, 38.0, 66.9,
168.1, 168.8 ppm; IR (KBr)
n
3056, 2983, 1745, 1320, 1111, 710 cmꢁ1
;
104.1, 111.1, 116.4, 119.1, 119.4, 122.2, 127.1, 135.9, 173.2, 177.4 ppm; IR
MS (CI) m/z 310 [MþH], 268, 243,141,122. C17H27NO4 (309.40) calcd
(KBr) n
3457, 3149, 2981, 1734, 1661, 1415, 1044 cmꢁ1; MS (EI) m/z
C 65.99, H 8.80, N 4.53; found C 65.81, H 8.66, N 4.78.
271 [Mꢂþ], 228, 171, 156, 130, 116; HRMS calcd for C16H17NO3 (Mþ)
271.1208, found: 271.1203.
4.2.4. Isopropyl 2-isopropoxycarbonyl-3-(N-benzylpyrrol-2-yl)-3-(2-
propyl)propanoate 3d. Pale yellow oil (3.5 g, 90%); 1H NMR
(300 MHz, CDCl3) 0.64 (d, J¼7.0 Hz, 3H), 0.76 (d, J¼7.0 Hz, 3H), 1.01
(d, J¼8.5 Hz, 3H), 1.07 (d, J¼8.5 Hz, 3H), 1.24 (d, J¼6.3 Hz, 3H), 1.26
(d, J¼6.3 Hz, 3H), 1.85 (m, 1H), 3.55 (dd, J¼10.8, 5.2 Hz, 1H), 3.69 (d,
J¼10.8 Hz, 1H), 4.78 (m, 1H), 5.08 (m, 1H), 5.12 (AB, J¼15.4 Hz, 2H),
5.92 (m, 1H), 6.06 (m, 1H), 6.46 (m, 1H), 7.22–7.34 (m, 5H); 13C NMR
4.2.10. (2S
panoate 4a. White solid (0.97 g, 45%); mp 128–130 ꢀC; 1H NMR
(300 MHz, CDCl3)
*
, 3R
*
)-Methyl 2-(acetyl)-3-(indol-3-yl)-3-(2-propyl)pro-
d
0.84 (d, J¼5.6 Hz, 6H), 1.90 (s, 3H), 2.05 (m, 1H),
3.78 (s, 3H), 3.88 (dd, J¼12.2, 3.8 Hz, 1H), 4.05 (d, J¼12.2 Hz, 1H),
6.89 (d, J¼2.4 Hz, 1H), 7.12 (m, 2H), 7.32 (d, J¼4.8 Hz, 1H), 7.67 (d,
J¼7.5 Hz, 1H), 8.14 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 17.2,
(75 MHz, CDCl3)
d
18.5, 21.1, 21.7, 21.8, 21.9, 31.4, 41.3, 50.7, 57.6,
21.9, 30.7, 41.9, 52.6, 64.8,111.1,111.9,119.2,119.6,122.2,128.2,135.6,
68.8, 69.1, 107.2, 107.6, 120.9, 127.7, 128.2, 128.8, 131.2, 138.4, 168.1,
169.8, 203.4 ppm; IR (KBr)
n 3277, 3048, 2977, 2951, 1727, 1696,
168.6 ppm; IR (KBr)
n
2976, 1749, 1473, 1259, 1101, 708 cmꢁ1; MS
1423, 1253 cmꢁ1; MS (EI) m/z 287 [Mꢂþ], 202, 170, 156, 130, 115;
(EI) m/z 399 [Mꢂþ], 356, 228, 212, 210, 168; HRMS calcd for
HRMS calcd for C17H21NO3Na 310.1419, found 310.1414.
C24H33NO4 399.2410, found: 399.2381.
4.2.11. (2S
noate 4b. Diastereomeric mixture (80/20); colorless oil (0.69 g;
49%); 1H NMR (300 MHz, CDCl3)
2.02 (s, 3H), 3.54 (s, 3H) (3.51),
*
,3R )-Methyl 2-(acetyl)-3-(indol-3-yl)-3-(phenyl)propa-
*
4.2.5. Methyl 2-methoxycarbonyl-3-(5-methoxycarbonyl-pyrrol-2-
yl)-3-(2-propyl)propanoate 3e. Orange solid (0.93 g, 34%); 1H NMR
d
(300 MHz, CDCl3)
d
0.82 (m, 6H), 0.88 (m, 1H), 3.33 (dd, J¼11.0,
4.51 (d, J¼11.8 Hz, 1H) (4.38), 5.10 (d, J¼11.8 Hz, 1H) (5.05), 7.02 (t,
4.5 Hz, 1H), 3.52 (s, 3H), 3.75 (s, 3H), 3.83 (s, 3H), 3.84 (d, J¼11.0 Hz,
J¼7.9 Hz, 1H), 7.08–7.32 (m, 8H), 7.50 (d, J¼7.7 Hz, 1H), 8.08 (s,
1H), 6.74 (m, 1H), 6.79 (m, 1H), 9.60 (s, 1H) ppm; 13C NMR (75 MHz,
1H) ppm; 13C NMR (75 MHz, CDCl3)
d 29.7, 42.8 (42.9), 52.6 (52.4),
CDCl3)
d
17.2, 21.5, 29.4, 43.9, 51.3, 52.2, 52.5, 55.7, 115.6, 121.6, 121.7,
65.6 (66.5), 111.2 (111.0), 117.2, 119.1, 122.3 (122.5), 126.5, 126.8,
122.7, 161.7, 168.5, 169.0 ppm; IR (KBr)
n
3322, 2955, 1702, 1437,
127.9, 128.3, 128.4, 128.6, 136.2, 141.1, 168.5, 202.2 ppm; IR (KBr) n
1210, 1135, 768 cmꢁ1; MS (EI) m/z 311 [Mꢂþ], 268, 180, 168; HRMS
3348, 3048, 2977, 2669, 1740, 1634, 1418 cmꢁ1; MS (EI) m/z 321
[Mꢂþ], 279, 265, 204, 173, 122; HRMS calcd for C20H19NO3 321.1365,
found 321.1356.
calcd for C15H21NO6 (Mþ) 311.1369, found: 311.1411.
4.2.6. Isopropyl 2-isopropoxycarbonyl-3-(imidazol-3-yl)-3-(2-pro-
pyl)propanoate 3f. Colorless oil (0.90 g, 33%); 1H NMR (300 MHz,
4.2.12. (2S
propanoate 4c. Diastereomeric mixture (50/50); pale yellow oil
(0.66 g, 41%); 1H NMR (300 MHz, CDCl3)
2.11 (s, 3H) (2.15), 3.52
*
, 3R
*
)-Methyl 2-(acetyl)-3-(indol-3-yl)-3-(2-nitrophenyl)-
CDCl3)
d
0.79 (d, J¼6.8 Hz, 3H), 0.91 (d, J¼6.8 Hz, 3H), 1.03 (d,
J¼6.3 Hz, 6H), 1.13 (d, J¼6.3 Hz, 3H), 1.26 (d, J¼6.3 Hz, 3H), 2.22 (m,
d

S. Ge´rard et al. / Tetrahedron 66 (2010) 3065–3069
3069
(s, 3H) (3.56), 4.40 (d, J¼12.1 Hz, 1H) (4.61), 5.91 (d, J¼12.1 Hz, 1H)
(5.98), 7.05–7.80 (m, 9H), 8.09 (s, 1H) (8.12) ppm; 13C NMR (75 MHz,
CDCl3) 28.2 (29.2), 36.1 (36.4), 52.2 (52.7), 65.6 (66.2), 111.1 (111.2),
114.1 (114.2), 119.2 (119.3), 119.7 (119.8), 122.3 (122.5), 122.6 (122.7),
124.3 (124.5),124.7 (125.0),127.2 (127.3),129.7 (129.9),132.5 (132.6),
Acknowledgements
d
Financial support from the French government and from the
‘French–Italian University’ to A.R. is gratefully acknowledged. This
work was also supported by CNRS. The authors thank P. Sigaut and
D. Patigny for mass-spectroscopic measurements and C. Petermann
for NMR analyses.
136.5(136.6),149.9(150.0),167.8(168.2), 201.4(201.9) ppm;IR(KBr)
n
3365, 3048, 2977, 2916, 1638, 1419 cmꢁ1; MS (EI) m/z 366 [Mꢂþ], 316,
218, 167, 149; HRMS calcd for C20H18N2O5 366.1216, found 366.1217.
References and notes
4.2.13. Methyl 1-isopropyl-3-methyl-1,4-dihydrocyclo penta[b]ind-
ole-2-carboxylate 5a. Pale yellow oil (0.56 g, 48%); 1H NMR
1. Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim,
2005.
(300 MHz, CDCl3)
d
0.37 (d, J¼6.8 Hz, 3H), 1.48 (d, J¼6.8 Hz, 3H),
2. For some recent reviews, see: (a) Orru, R.; De Greef, M. Synthesis 2003, 1471–
1499; (b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80; (c) Simon, C.;
Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–4980; (d) Ramon,
D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634; (e) Domling, A. Chem.
Rev. 2006, 106, 17–89.
3. (a) Reetz, M. T. In Organometallics in Synthesis a Manual, 2nd ed.; Schlosser, M.,
Ed.; John Wiley: New York, NY, 2002; pp 817–923; (b) Reetz, M. T.; West-
ermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek, R.; Maus, S. Chem.
Ber. 1985, 118, 1421–1440; (c) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16,
817–826; (d) Fu¨rstner, A.; Bogdanovic´, B. Angew. Chem., Int. Ed. 1996, 35,
2442–2469; (e) Weidmann, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1983, 22,
31–45; (f) Sana, S. Synlett 2002, 364–365.
4. (a) Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880–2881.
5. (a) Ghosh, A. K.; Xu, C.-X.; Kulkarni, S.; Wink, D. Org. Lett. 2005, 7, 7–10; (b)
Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40, 1083–1086; (c) Ghosh, A.
K.; Kawahama, R. Tetrahedron Lett. 1999, 40, 4751–4754; (d) Kim, S. H.; Wei, H.-
X.; Gao, J. J.; Li, G. Molecules 2002, 7, 89–95; (e) Kalinski, C.; Lemoine, H.;
Schmidt, J.; Burdack, C.; Kolb, J.; Umkehrer, M.; Ross, G. Synthesis 2008, 24,
4007–4011.
2.53 (s, 3H), 2.82 (m,1H), 3.78 (m,1H), 3.85 (s, 3H), 7.16 (m, 2H), 7.41
(d, J¼8.5 Hz, 1H), 7.70 (d, J¼7.2 Hz, 1H), 8.29 (s, 1H) ppm; 13C NMR
(75 MHz, CDCl3) d 13.1, 15.8, 23.1, 28.4, 50.9, 52.6, 112.2, 120.4, 121.1,
122.2, 124.7, 126.2, 135.2, 141.1, 143.8, 146.7, 165.9 ppm; IR (KBr)
n
3356, 3048, 2986, 1652, 1264 cmꢁ1; MS (EI) m/z 269 [M$þ], 254,
238, 210, 194, 167; HRMS calcd for C17H19NO2 269.1416, found
269.1412.
4.2.14. Methyl 1-phenyl-3-methyl-1,4-dihydrocyclopenta[b]indole-2-
carboxylate 5b. Yellow oil (0.11 g, 34%); 1H NMR (300 MHz, CDCl3)
d
2.27 (s, 3H), 3.84 (s, 3H), 6.72 (s, 1H), 7.18–7.55 (m, 5H), 7.61–
7.88 (m, 4H), 7.95 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d
14.2,
50.8, 52.9, 111.5, 113.9, 118.1, 119.9, 122.5, 122.6, 122.8, 123.0,
123.7, 124.7, 127.5, 129.1, 132.5, 136.4, 167.1 ppm; MS (EI) m/z 303
[Mꢂþ], 288, 229, 226; HRMS calcd for C20H17NO2 303.1259, found
303.1266.
6. Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 20, 1759–1762.
´
´
7. (a) Dardennes, E.; Kovacs-Kulyassa, A.; Renzetti, A.; Sapi, J.; Laronze, J.-Y. Tet-
rahedron Lett. 2003, 44, 221–223; (b) Cochard, F.; Laronze, M.; Sigaut, P.; Sapi, J.;
Laronze, J.-Y. Tetrahedron Lett. 2004, 45, 1703–1708.
4.2.15. Methyl 1-(2-nitrophenyl)-3-methyl-1,4-dihydro cyclopenta[b]
´
´
8. (a) Dardennes, E.; Kovacs-Kulyassa, A.; Boisbrun, M.; Petermann, C.; Laronze,
indole-2-carboxylate 5c. Pale yellow oil (0.27 g, 77%); 1H NMR
J.-Y.; Sapi, J. Tetrahedron: Asymmetry 2005, 16, 1329–1339; (b) Jeannin, L.;
´
Boisbrun, M.; Nemes, C.; Cochard, F.; Laronze, M.; Dardennes, E.; Kovacs-Ku-
(300 MHz, CDCl3)
(m, 5H), 7.51–7.75 (m, 2H), 7.84 (m, 1H), 8.05 (s, 1H) ppm; 13C NMR
(75 MHz, CDCl3) 14.8, 51.2, 52.4, 111.3, 114.5, 118.3, 119.7, 122.5,
122.6, 123.7, 124.7, 127.5, 129.1, 132.6, 136.3, 148.9, 166.9 ppm; IR
d 2.50 (s, 3H), 3.66 (s, 3H), 6.68 (s, 1H), 7.25–7.43
´
lyassa, A.; Sapi, J.; Laronze, J.-Y. C.R. Chim. 2003, 6, 517–528 and references cited
therein.
d
´
9. Renzetti, A.; Dardennes, E.; Fontana, A.; De Maria, P.; Sapi, J.; Gerard, S. J. Org.
Chem. 2008, 73, 6824–6827.
(KBr)
n
3048, 2977, 2951, 1696, 1415, 1252 cmꢁ1; MS (EI) m/z 348
10. Katrizky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry; Pergamon:
Amsterdam, 2000; p 321.
11. Lieby-Muller, F.; Simon, C.; Constantieux, T.; Rodriguez, J. QSAR Comb. Sci. 2006,
25, 432–438.
[Mþ], 333, 302, 289, 226, 122; HRMS calcd for C20H16N2O4 348.1110,
found 348.1121.
12. (a) Brown, R.; Coulston, K.; Eastwood, F.; Moffat, M. Tetrahedron 1992, 48,
7763–7774; (b) Miura, T.; Harumashi, T.; Murakami, M. Org. Lett. 2007, 9,
741–743; (c) Feldman, K.; Hester, K., II; Iyer, M.; Munson, P.; Lopez, C. S.; Faza,
O. N. J. Org. Chem. 2009, 74, 4958–4974.
4.3. Procedure for the enolate formation test
13. Marrone, A.; Renzetti, A.; De Maria, P.; Ge´rard, S.; Sapi, J.; Fontana, A.; Re, N.
To a solution of Ti(O-iPr)4 (0.5 equiv) in CDCl3 (700
mL) were
Chem. Eur. J. 2009, 15, 11537–11550.
14. Pure 4a could be partially epimerized under kinetic conditions (0 ꢀC) by
treatment with Et3N (for details, see Ref. 9).
added subsequently TiCl4 (0.5 equiv), diisopropyl malonate
(1.0 equiv), Et3N (1.0 equiv), and DCl/D2O 35% (3.0 equiv). After
each addition 1H NMR and 13C NMR spectra were recorded. The
concentration of Ti(Oi-Pr)4 in CDCl3 was 2.19ꢃ10ꢁ2 M.
15. (a) Reetz, M. T.; Kesseler, K.; Schimdtberger, S.; Wenderoth, B.; Steinbach, R.
Angew. Chem., Int. Ed. Engl. 1983, 22, 989–990; (b) Rossi, T.; Marchioro, C.; Paio,
A.; Thomas, R. J.; Zarantonello, P. J. Org. Chem. 1997, 62, 1653–1661.